Hydrogel

ABSTRACT

A method of preparation of a cross-linked hydrogel by graft copolymerisation, said method comprises the steps of preparing an aqueous solution comprising one or more hydrophilic polymers, a cross-linking agent and a photoinitiator comprising a water-soluble peroxydisulphate, subjecting said solution to irradation and obtaining the cross-linked hydrogel, wherein the hydrophilic polymers are saturated and the cross-linking agent acts as a co-catalyst of cross-linking. The hydrogel is fast to produce and has low toxicity. The hydrogel may be suitable for use in medical devices such as dressings and the like.

This is a nationalization of PCT/DK03/000655 filed Oct. 2, 2003 andpublished in English.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a cross-linked hydrogel and thepreparation a hydrogel, a solution for the preparation of a hydrogel anda hydrogel sheet.

2. Background of the Invention

Free radical, network-producing polymerisations are used in a variety ofapplications including coatings, information storage systems, films, andaspherical lenses and biomaterials.

Cross-linked hydrogels are commonly prepared by free radicalpolymerisation. Over the past three decades, a number of hydrogelsdiffering in structure, composition, and properties have been developed.Hydrogels are insoluble, water-swollen networks composed of hydrophilichomo-or copolymers. They are desirable for biomedical applicationsbecause of their high water content and rubbery nature, similar tonatural tissue.

Free radical polymerisation processes are initiated by free radicalinitiators to obtain ensure proper polymerisation rates. These freeradical initiators are activated by irradiation e.g. in the form ofE-beam, microwaves, gamma or light (which includes UV, visible or nearinfrared). Other methods of initiating free radical polymerisation arethermal initiation and redox initiation.

While all initiation methods have their advantages/disadvantages the useof photopolymerisation is recognized as a fast, convenient andcontrollable way of preparing hydrogels through free radicalpolymerisation. The polymerisation process can be carried out underambient or physiological conditions and even in the presence ofbiologically active materials. There are other advantages of using thephotopolymerisation technique for biomaterials. In general, the processis benign and the process may also proceed rapidly at ambient conditionsfor most monomers and conventional initiators, i.e. fast curing rates.In addition, the ability to direct exposure of for example UV light andtime of incidence to achieve spatial and temporal control isparticularly advantageous for the formation of complex devices.

Due to their biocompatibility, permeability, and physicalcharacteristics, hydrogels are suitable for use in many medicalapplications, including tissue engineering. Hydrogels may be useful formanipulation of tissue function or for scaffolds for tissue regenerationor replacement. The use of photopolymerisation in the preparation ofhydrogels is advantageous in comparison with conventional cross-linkingmethods because liquid hydrogels precursors can be delivered andcross-linked to form hydrogels in situ in a minimally invasive manner.This process also renders it possible to achieve spatial and temporalcontrol over the conversion of a liquid to a gel, so that complex shapescan be fabricated. Hydrogels can be formed with varying polymerformulations in three-dimensional patterns since sequentiallypolymerised layers will firmly adhere to one another.

Photopolymerised hydrogels can be designed to degrade via hydrolytic orenzymatic processes and can be modified with biofunctional moietieswithin their structure to manipulate cell behaviour and to generateorgan-specific tissue formation. These photopolymerisable hydrogels canbe used as barriers, localized drug delivery depots, cell encapsulationmaterials, and scaffold materials. Other biomedical applications includethe prevention of thrombosis, post-operative adhesion formation, drugdelivery, coatings for biosensors, guide-wires and catheters, and forcell transplantation.

Visible or UV light can interact with light sensitive compounds calledphoto-initiators to create free radicals that can initiatepolymerisation to form cross-linked hydrogel (3-D polymeric networks).In vivo this principle has been utilized to polymerise or cure materialsin dentistry to form sealant and dental restorations in situ.Photopolymerisations has also been used in electronic materials,printing materials, optical materials, membranes, polymeric materials,and coatings and surface modifications.

Photopolymerisation has several advantages over conventionalpolymerisation techniques. These include spatial and temporal controlover polymerisation, faster curing rates (less than a second to a fewminutes) at room or physiological temperature, and minimal heatproduction. Furthermore, photopolymerisation can be utilized to createhydrogels in situ from aqueous precursors in a minimal invasive manner.Fabrication of polymers in situ is attractive for a variety ofbiomedical applications because this allows one to form complex shapesthat adhere and conform to tissue structures, for example laparascopicdevices, catheters, or subcutaneous injection with trans-dermalillumination.

Polymerisation conditions for in vivo applications are however difficultsince biological systems require a narrow range of acceptabletemperatures and pH, as well as absence of toxic materials such asmonomers and organic solvents is demanded. Some photopolymerisationssystems may overcome these limitations because the polymerisationconditions are sufficiently mild (low light intensity, short irradiationtime, physiological temperature, and low organic solvent levels) to becarried out in the presence of cells and tissues.

Photopolymerisation schemes generally use a photoinitiator that has ahigh absorption at a specific wavelength of light to produce radicalinitiating species. Other factors that should be considered include itsbiocompatibility, solubility in water, stability, and cytotoxicity.Various photoinitiators have been investigated to achieve betterphotopolymerisation. Photoinitiation is classified in three majorclasses depending on the mechanism involved in photolysis. The classesare radical photopolymerisation trough 1) photo-cleavage, 2) hydrogenabstraction and 3) cationic photopolymerisation. Cationicphotoinitiators are generally not utilized in tissue engineeringapplications because they generate protonic acids and toxic sideproducts. Cationic photopolymerisation will not be discussed furtherhere.

In radical photopolymerisation by photocleavage, the photoinitiatorsundergo cleavage at C—C, C—Cl, C—O, or C—S bonds to form radicals whenexposed to light. Water-soluble photoinitiators include aromaticcarbonyl compounds such as benzoin derivatives, benziketals,acetophenone derivatives, and hydroxyalkylphenones. Acetophenonederivatives that contain pendant acrylic groups have been shown tosubstantially reduce the amount of unreacted photoinitiator with nosignificant loss in the initiation efficiency. Acetophenone derivatives,such as, 2,2-dimethoxy-2-phenyl acetophenone, have been used asphotoinitiators to form hydrogels from acrylated polyethylene glycol(PEG) derivatives in several biomaterial studies.

Radical photopolymerisation by hydrogen abstraction: When subjected toUV irradiation, photoinitators such as aromatic ketones (i.e.,benzophenone and thioxanthone) undergo hydrogen abstraction from anH-donor molecule to generate a ketyl radical and a donor radical. Theinitiation of photopolymerisation usually occurs through the H-donorradical while the ketyl radical undergoes radical coupling with thegrowing macromolecular chains. The photoinitiator propyl thixanthone hasbeen shown to be cytocompatible.

Effective photoinitiators are for example compounds such asbenzophenone, acetophenone, fluorenone, benzaldehyde, propiophenone,anthraquinone, carbazol, 3 or 4-methylacetophenone, 3 or4-methoxybenzophenone, 4,4′-dimethoxybenzophenone, allylacetophenone,2,2′-diphenoxyacetophenone, benzoin, methylbenzoin ether, ethylbenzoinether, propylbenzoin ether, benzoin acetate, benzoinphenyl carbamate,benzoin acrylate, benzoinphenyl ether, benzoyl peroxide, dicumylperoxide, azo isobutyronitrile, phenyl disulphide, acyl phosphene oxideor chloromethyl anthraquinone as well as mixtures thereof.

Peroxy—compounds, i.e. compounds containing an —O— binding, where oxygenhas the oxidation number −1 are known as strong oxidation agents. Theyare capable of producing free radicals in many environments. As suchperoxy-compounds have been utilized in free radical polymerisations asinitiators of various kind, i.e. thermal, photo or redox initiation.

Persulphate (peroxydisulphate) is well known as an initiator of vinylpolymerisation in aqueous systems. Often used as a thermal initiator,where thermal decomposition produces radical ions, which directly orindirectly cause chain propagation. Peroxides may also be used asphotoinitiators of vinyl polymerisation processes; both hydrogenperoxide, peroxydisulphate and peroxydiphosphate have been utilized forthis purpose. The reaction scheme for the initiation ofperoxydisulphates by photodecomposition is similar to that of thermalinitiation. From the reaction scheme it is evident that the sulphate orhydroxyl radicals or a combination thereof may initiate polymerisation.

The peroxydisulphate is decomposed into sulphate ion radicals. Theseradicals are capable of reacting with a macromer or monomer unit(denoted M) to create a macromer or monomer radical. Furthermore thesulphate ion radical is capable of hydrogen abstraction from water thuscreating hydroxyl radicals, which may react with a macromer or monomerunit creating another macromer or monomer radical.S₂O₈ ⁻+(ΔOR hv)→2SO₄ ^(●−)SO₄ ^(●−)+M→⁻SO₄M.SO₄ ^(●−)+H₂O→HSO₄ ⁻+HO.HO.+M→HOM.

It is also well known that decomposition can be induced by the additionof reducing agents such as ferrous ions:Fe²⁺+S₂O₈ ²⁻→Fe³⁺+SO₄ ²⁻+SO₄ ^(●−)

Peroxydisulphates have commonly also been employed in irradiationpolymerisation processes where irradiation with γ rays are used. Anotherprocess concerned with the chemistry of peroxides has proven useful infree radical polymerisation, namely the photo-Fenton reaction. Thephoto-Fenton reaction has been largely applied in oxidative degradationof organic pollutants for water treatment and in some special casesdepolymerisation technique. The photo-Fenton reaction has also beendescribed to produce polymers from vinylpyrrolidone (VP) and copolymershereof (copolymers of VP and MAA (methacrylic acid).

The photo-Fenton reaction is a process comprising two-interconnectedsteps. Firstly, hydrogen peroxide is decomposed into hydroxyl radicalsby the presence of Fe²⁺, which is oxidized to Fe³⁺. In the dark thereaction is retarded after complete conversion of Fe²⁺to Fe³⁺.Irradiation of the system by UV-light (around 365 nm) results inphotoreduction of Fe³⁺ to Fe²⁺, which produce new hydroxyl radicals withhydrogen peroxide according to the first process or to an additionaleffect of direct peroxide photolysis. In the above mentionedpolymerisation process practically no polymerisation occurred withoutlight. Hence, to create a high enough concentration of hydroxyl radicalsto initiate chain propagation, light is necessary.

It is believed, that any free radical initiation system, especially freeradical polymerisations carried out in aqueous solutions capable ofgenerating soluble peroxides may be greatly enhanced by the addition ofsoluble metal ions capable of initiating the decomposition of the formedperoxides (redox process). These metal ions include iron and othertransition metals having at least to readily available oxidation states.

Polymerisation of monomers using visible or UV irradiation has beenthoroughly investigated. While such systems may work well for manyapplications including many biomaterials, they generally cannot beutilized in tissue engineering because most monomers are cytotoxic. As aresult, photopolymerisable hydrogels for tissue engineering havegenerally been formed from macromolecular hydrogel precursors. Suchprecursors are water-soluble polymers with two or more reactive groups.Examples of photopolymerisable macromers include PEG acrylatederivatives, PEG methacrylates derivatives.

Poly(ethylene glycol) is a non-toxic, water soluble polymer whichresists recognition by the immune system. The term PEG is often used torefer to polymer chains with molecular weights below 20.000, whilepoly(ethylene oxide) (PEO) refers to higher molecular weight polymers.PEG may transfer its properties to another molecule when it iscovalently bound to said molecule. This may result in toxic moleculesbecoming non-toxic (as is the case with PEG-DMA which is non-toxicpegylated dimethacrylic acid) or hydrophobic molecules becoming solublewhen coupled to PEG. It exhibits rapid clearance from the body, and hasbeen approved for a wide range of biomedical applications. Because ofthe properties, hydrogels prepared from PEG are excellent candidates asbiomaterials.

Polyvinyl alcohol (PVA) derivatives, and modified polysaccharides suchas hyaluronic acid derivatives and dextran methacrylate have beendescribed as useful macromolecular precursors.

Polyvinylpyrrolidone (PVP) is another useful candidate. Polymericmaterials based on poly(N-vinyl-2-pyrrolidone) (PVP) and its copolymershave found intense applications as hydrogels and membranes used in drugdelivery systems, adhesive formulations, and in photographic andlithographic coatings. The low chemical toxicity of PVP, its solubilityin water and in organic solvents as well as its ability to complex withmany kind of substrates like dyes, surfactants, and other polymers, havepromoted its use as a protective colloid in pharmaceutical and cosmeticproducts.

3. Description of the Related Art

U.S. Pat. No. 5,410,016 discloses the development of photopolymerisablebiodegradable hydrogels. The hydrogel comprises a macromer on which isgrafted biodegradable units such as poly(alpha-hydroxy acid),poly(glycolic acid), poly(DL-lactic acid) and poly(L-lactic acid). Otheruseful materials includes poly(amino acids), poly(anhydrides),poly(orthoester), poly(phosphazines) or poly(phosphoester). Polylactoneslike poly(ε-caprolactone), poly(δ-valerolactone) orpoly(λ-butyrolactone).

PVP is mentioned as a possible water-soluble region of the macromer.Acrylates, diacrylates, oligoacrylates, methacrylates, dimethacrylates,oligomethacrylates are mentioned as polymerisable regions of themacromer. The macromers are synthesized in organic solvents andphotosensitive macromers prepared from these macromers. A combination ofPEG-DMA and PVP is mentioned, the photoinitiators employed are commonlyknown. Peroxydisulphates may alternatively be used as thermalinitiators.

U.S. patent application No. 2001/0044482 discloses interpenetratingpolymer network (IPN) compositions and a process for the manufacturingof hydrogel contact lenses. The polymeric material is prepared bypolymerisation of an unsaturated alkyl(meth)acrylate or its derivativessuch as 2-hydroxyethyl methacrylate (HEMA) as the principle monomer,optionally vinyl containing comonomer(s) to enhance the resulting waterabsorbing capability, polymerisable multi-functional cross-linkingagent(s), an irradiation initiator and/or thermal initiator, optionallyother additives to impart the resulting hydrogel specific propertiessuch as UV-blocking ability and handling colorants; in the presence of asoluble hydrophilic interpenetrating networking agent such aspolyvinyl-pyrrolidone or poly-2-ethyl-2-oxazoline (PEOX) with a specificmolecular weight. PVP is mentioned as IPN agent, PEG-DMA is mentioned asa cross-linker and photoinitiation or/and thermal polymerisation ismentioned. UV or thermal initiation is used alone or in combination.

The hydrogels are prepared by mixing all the ingredients (dissolved ineach other), subjecting the mixture to a short UV curing (minutes)followed by a longer thermal post curing (hours). The obtained dry gelis then hydrated after curing. The method of preparation is used inorder to obtain a thorough curing process to secure that all monomershave been consumed in the curing process. The curing process is quitetime consuming.

U.S. Pat. No. 5,005,287 discloses a process for forming and applying ahydrophilic coating cured by UV-light to a plastic or metal part eitherdirectly, or indirectly via plastic film, to safety razor or razor bladeunit. The coating comprises a water-soluble polymer or copolymer of PVP,at least one radically polymerisable vinyl monomer and a photoinitiator.Several vinylic monomers, mostly of the type acrylic acid or methacrylicacids are mentioned. Oligoethylene glycol bisacrylate is mentioned as asuitable cross-linker. A wide range of photoinitiators is mentioned.Water is mentioned as a polymerisation solvent. The cured polymer layersare of 5-1000 μm thickness. Curing times are in seconds to minutes.

W. K. Wilmarth and A. Haim in J. O. Edwards (ed.), Peroxide reactionmechanisms, Wiley-Interscience, New York, 1962, pp. 175-225, disclosesthe reactions of peroxidisulphate with various substrates in aqueoussolution from a mechanistic viewpoint. The thermal and photolyticdecompositions of the peroxidisulphate ion are described in detail.

C. G. Roffey in JOCCA 1985 (5), 116-120, discloses thephotodecomposition of the peroxydisulphate ion in water or water/ethanolmixtures producing sulphate ion radicals, which are potentially usefulin various emulsion polymerisation techniques.

S. Lenka and P. L. Nayak in Journal of Photochemistry, 1987, 36,365-372, disclose the use of peroxydiphosphate to photopolymerise methylmethacrylate.

In-Sook Kim et al, in Arch. Pharm. Res. 2001, 24, No. 1 69-73 disclosesthe use of ammonium peroxydisulphate and UV light in vinylic radicalpolymerisation of a biodegradable hydrogel formed from a functionaliseddextran (glycidyl methacrylate dextran and dimethacrylate poly(ethyleneglycol). The photopolymerisation process is carried out with a ratherhigh amount of ammonium persulphate (10% of polymer weight) and a verylong UV-curing time of 80 minutes.

Thus, there is still a need for a hydrogel, which can be produced in afast and simple manner, being non-toxic and producible in both thin andthick layers. Surprisingly, such a hydrogel has been achieved by thepresent invention.

SUMMARY OF THE INVENTION

It is the first object of the invention to prepare a cross-linkedhydrogel in a fast and simple manner.

It is another object of the invention to prepare a non-toxic hydrogel.

It is further an object of the invention to prepare a hydrogel ofvarious shapes and thickness.

The present invention relates to a cross-linked hydrogel, thepreparation of such hydrogel, a stock solution for preparing a hydrogeland a hydrogel sheet material.

DETAILED DESCRIPTION OF THE PRESENT INVENTION

The invention relates to a method of preparation of a cross-linkedhydrogel by graft copolymerisation, said method comprises the steps ofpreparing an aqueous solution comprising one or more hydrophilicpolymers, a cross-linking agent and a photoinitiator comprising awater-soluble peroxydisulphate, subjecting said solution to irradiationand obtaining the cross-linked hydrogel, wherein the hydrophilicpolymers are saturated and the cross-linking agent acts as a co-catalystof cross-linking.

The peroxidisulphate may preferably be sodium, potassium or ammoniumperoxydisulphate.

The invention further relates to a composition for preparation of across-linked hydrogel by graft copolymerisation, said compositioncomprises an aqueous solution comprising one or more hydrophilicpolymers, a cross-linking agent and a photoinitiator comprising aperoxysulphate, wherein the hydrophilic polymers are saturated and thecross-linking agent acts as a co-catalyst of cross-linking.

The invention relates to a method for preparing a hydrogel (a threedimensional cross-linked hydrophilic copolymer network) in a fast,efficient photo-curing method. This is obtained usingphoto-polymerisation in aqueous solution through combined graftcopolymerisation and cross-linking employing photopolymerisable watersoluble hydrophilic saturated polymers and cross-linking agents ashydrogel precursors and water soluble peroxy compounds asphotoinitiators alone or in combination with co-initiators (such asphoto-Fenton like catalysis). The resulting hydrogel network is a watercontaining grafted and cross-linked polymer network.

The chemistry of the photodecomposition of peroxidisulphate is welldescribed in literature and the utilization of this initiating reactionin free radical polymerisations has been disclosed. The use ofperoxidisulphate as an photoinitiator has primarily been for vinylpolymerisation processes, i.e. for initiating free radicalpolymerisations from unsaturated monomers, i.e. monomers containingvinylic or acrylic groups, such groups reacting willingly with theinitiating sulphate ion radicals creating new propagating radicals.

Surprisingly, it has in the present invention been found thathydrophilic saturated polymers in aqueous solution, i.e. polymerscontaining no available (free) vinyl or acrylic groups, can be activatedby the photodecomposition of peroxidisulphate leading to the creation offree polymer radicals through hydrogen abstraction which in turn leadsto a cross-linked hydrogel by a grafting process. The cross-linking isin turn a combination of polymer radicals combining with each other andpolymer radicals initiating a graft copolymerisation with thecross-linking agent, both forming a cross-linked network.

The main polymerisation process may be described as follows: Whensubjected to UV irradiation, a peroxy-containing compound such asperoxydisulphate, the resulting sulphate ion radical is capable ofeither hydrogen abstraction from the saturated hydrophilic polymerpresent in solution or creating a cross-linking agent radical. It mayalso terminate by reacting with other free radicals. The polymerradicals can combine with each other or initiate a graftcopolymerisation by combining with cross-linking agent radicals. Theoverall cross-linking is a mix of cross-links between polymer-polymer,polymer and grafted polymer and polymer-cross linking agent. The maincontribution of cross-links will be from polymer-polymer cross-links.The end result is a hydrogel consisting of grafted cross-linked polymernetwork containing water.

The curing efficiency of the system presented is beyond what would beexpected using the described amounts of cross-linking agent andphotoinitiator. While it is quite possible to cross-link a hydrophilicsaturated polymer itself like PVP using large amounts of photoinitiatorand a heavy dose of heat or irradiation, it is surprising to find acuring speed, curing effienciency and resulting gel strength as high aspresented from the compositions employed in the present invention.Theoretically, in the present invention, the cross-linking agent itselfcould be incorporated into the polymeric network contributing to theoverall curing efficiency. However, the double bond density defined bythe amount of cross-linking agent employed and thus defining the finalcross-linking density is much to small to explain the resulting curingspeed, efficiency and gel strength.

The curing efficiency of the present method may be subscribed to apreferred combination of peroxydisulphate acting as the photoinitiatorand the cross-linking agent having a dual function, namely both being across-linker itself and acting as co-catalysator of cross-linking. Thus,obtaining the grafted cross-linked hydrogel requires apart from thehydrophilic saturated polymer in solution only the presence of acatalytic amount of an unsaturated cross-linking agent and small amountof photoinitiator (peroxidisulphate).

Still further, the photopolymerisation method offers a safe andconvenient way of preparing a cross-linked hydrogel by simply mixing theconstituents and curing the solution in a free radical bulk solutionphotopolymerisation process under ambient conditions. The hydrogelaccording to the invention may be prepared in industrial scale via asimple in-line process or it may be prepared in situ under physiologicalconditions (in vivo or in vitro). The use of the photopolymerisationmethod according to the invention allows hydrogels to be prepared bothin stock rolls and in complex shapes using moulding. Due to thephotopolymerisation technique employed in this invention it is possibleto obtain deep curing of polymer solutions obtaining hydrogels ofvarious thickness from very thin (μm) to very thick layers (severalcentimeters). Hydrogels with a broad range of properties including avarying degree of adhesiveness may be prepared.

The hydrogel of the invention may preferably be prepared as sheets orcoatings, in a continuous process or in bulk production. The sheet mayhave any suitable thickness such as from 10 μm to 2 cm.

In one embodiment of the invention the hydrogel is casted in a mold toobtain a three-dimensional configuration.

Hence, the hydrogel according to the present invention may be preparedfor a vast number of various fields such as wound dressings, controlledrelease (drug delivery) devices including transdermal drug deliverydevices, cosmetics, biosensors or electrodes, coatings or membranes.Included are hydrogels as skin adhesives and protectants for instancefor ostomy and continence care.

The method according to the invention allows the preparation of anon-toxic and biocompatible hydrogel through the use of safe andnon-toxic constituents. The resulting hydrogel has due to the nature ofthe method of preparation, i.e. the efficiency of the photoinitiatingsystem, the employment of macromolecular hydrogel precursors andcatalytic amounts of cross-linking agent and photoinitiator, a very lowcontent of residuals and may be used for biological or medical purposeswithout the need of drying, washing and rehydration to remove anyundesired content of residuals as is necessary and common practice whenpolymerising from monomers which often are toxic.

A preferred embodiment of the invention relates to a cross-linkedhydrophilic polymer network system, said hydrogel comprising ahydrophilic water-soluble polymer PVP or copolymers of PVP, grafted andcross-linked with a suitable cross-linking agent.

The hydrogel is prepared in aqueous solution through a free radical bulksolution polymerisation using photopolymerisation with wavelengths from190-1000 nm, preferably 200-700 nm. The polymerisation is brought aboutby the decomposition of a water-soluble photoinitiator into freeradicals, which directly or indirectly cause chain propagation andcross-linking. The critical property of the photoinitiating system isthat the polymerisation will not proceed at a useful rate without thepresence of the initiator.

The photocuring method disclosed in the present invention issurprisingly fast and efficient. The hydrophilic saturated polymers, thecross-linking agent and the photoinitiator are mixed in an aqueoussolvent and cured by light obtaining a water containing a grafted andcross-linked hydrogel system. The curing is rapid in the range ofseconds to minutes depending of the desired thickness of the hydrogel.Deep complete curing can be obtained allowing very thick layers (severalcentimeters) of hydrogel to be prepared.

The method of the present invention is superior to commonphotopolymerisation processes due the capability of a very effectivedeep curing (μm—several centimeters) in a short period of time (secondsto minutes) in solutions containing from a very low to a very highamount of water. The photocuring may be carried out in air under ambienttemperature and pressure.

UV initiated photopolymerisations are often slow in air compared to inan inert atmosphere. However, the photopolymerisation process accordingto the invention is seemingly not impaired by the presence of oxygen.Oxygen, which often inhibits free radical reactions, which inhibitpropagation, does surprisingly not slow down the polymerisation processin the in method according to the invention to any critical extent andthe insensibility to oxygen contributes to an efficient curing. The timerequired for gelation is short (seconds to minutes depending onthickness). This is very significant. No significant difference in thepolymerisation rates and the physical/mechanical properties of thehydrogel is observed in hydrogels produced in air compared to hydrogelsprepared in an inert atmosphere created by purging the solutions withnitrogen. However, to minimize the effect of any created peroxides dueto dissolved oxygen in the aqueous solutions, which potentially couldinfluence the stability of the resulting hydrogel, Fe²⁺ may be addedalone or in combination with one or more antioxidants like ascorbic acidto enhance the free radical initiating system.

Further distinctions from other systems using UV-curing free radicalpolymerisation and peroxydisulphates and/or the ferrous co-initiatorsystem may be made. For example it should be noted that it is notpossible to obtain a strong gel network in the following cases:

a) By thermal initiation, i.e. introducing the aqueous solution to heat(80° C.) in the same time span as in which the aqueous solutions isirradiated with UV-light. A thermal initiated gelation withperoxydisulphate would usually have a time span of hours,

b) by decomposition of the peroxydisulphate with a ferrous ion intosulphate radicals. The presence of a reducing agent like the ferrous ion(Fe²⁺) or a redox pair like ascorbic acid and Fe²⁺ together withperoxydisulphate is not enough to create a useful and satisfyinghydrogel network. It is necessary to irradiate the polymer solution withlight simultaneously to obtain a strong cross-linked hydrogel,

c) by leaving out the cross-linking agent. Peroxydisulphate cross-linkedPVP gels have been described using either thermal initiatedpolymerisation or irradiation (γ rays). Furthermore, it has beendescribed that aqueous PVP solutions could be directly cross-linked byirradiation with γ rays. In the present method no curing is seen wheneither PEG-DMA or peroxydisulphate or both are left out of the solution.Both are necessary for the formation of strong but soft hydrogelmaterial.

When replacing the peroxydisulphates with other commonly usedwater-soluble photoinitiators and curing under identical conditions onlya partly (surface) cured hydrogel may be obtained.

The hydrophilic saturated polymers may be selected from the group ofcellulose derivatives, polysaccharides, polyvinyl-pyrrolidone, polyvinylalcohol, polyacrylic acid, poly(methyl vinyl ether/maleic anhydride),poly(meth)acrylic acid, polethylenglycols (PEG), polyamides, polyacrylicamides, polyethylene glycol (PEG) or copolymers or blends of these.

A primary issue for the hydrophilic polymer is toxicity and watersolubility. For all biologically related uses toxicity must be low orabsent in the finished hydrogel. Thus, the hydrophilic polymers shouldnot be harmful and should be non-toxic. Choosing a hydrophilic saturatedpolymer from the above list ensures that the entry level of unwanted ortoxic residuals are kept very low.

In a preferred embodiment of the invention the hydrophilic polymerscomprise polyvinyl pyrrolidone (PVP) or PVP based copolymers.

The principle hydrophilic polymer is preferably polyvinyl pyrrolidone(PVP) or PVP based copolymers in order to obtain a hydrophilic,water-soluble polymer backbone. The amount of polymer used is preferablyin the range 1-90% w/w more preferred in the range of 5-50% w/w,depending on the water content and other desired properties of theresulting hydrogel.

The cross-linking agent may comprise vinylic or unsaturated macromers ormonomers such as mono-/di- or multifunctional acrylates ormethacrylates.

The term “cross-linking agent” is used herein in a broad sense in thatit is a composition, which is capable of being grafted to the polymericbackbone and ensuring cross-linking of the polymeric backbone, either bysolely catalysing a cross-linking reaction between the hydrophilicpolymer chains or by becoming a part of the resulting polymeric network.

Typically, the cross-linkers are di- or multifunctional compounds thatcan incorporate themselves into the resulting polymer backbone duringthe polymerisation process. The cross-linking agent may comprise vinylicor unsaturated macromers or monomers.

The concentration of the cross-linking agent is chosen according to therequired degree of cross-linking, and consequently it is determined notonly by the amount of the cross-linking agent but also by the type andability to form the cross-linked polymer. The less effectivecross-linking agents have to be applied in a higher concentration thanthe more effective ones. While the cross-linker in principle could beadded in very high concentrations up to approximately 80% w/w of polymerweight, preferably, the cross-linking agents may be present in an amountof 1- to 30% w/w of polymer weight, more preferred 1-25% w/w, even morepreferred 1-20% w/w, and most preferred 1-15% w/w In one embodiment ofthe invention the cross-linking agent is present in an amount of up1-10% w/w of polymer weight.

When referring to the cross-linking agent as a co-catalysator ofcross-linking, it should be perceived that the concentrations inquestion are fairly low concentrations as the double bond density insolution and thus the cross-linking density of the cross-linking agentitself in the resulting polymer network would be low. Too low to explainthe curing efficiency of the method presented in the invention. This isaccordance with the principle that the cross-linking agent primarilyacts as a co-catalysator of the cross-linking process as much as being across-linker itself.

The cross-linking agent may include, but are not being limited to,cyclic or open-chain ether groups, such as esters of single or multipleethoxylated or propoxylated C.sub.1-C.sub.20 alcohols, tetrahydrofuran(“THF”) carbinol acrylate or THF carbinol methacrylate, hydroxyalkylesters, such as 2-hydroxyethyl acrylate, 2-hydroxyethyl methacrylate,2-hydroxypropyl acrylate or 2-hydroxypropyl methacrylate,N,N-dimethylamino-2-hydroxyethyl acrylate,N,N-dimethylamino-2-hydroxyethyl acrylate, N,N-dimethylaminoethylmethacrylate or salts thereof, such as N,N,N-trimethylammonium-2-ethylmethacrylate chloride, also acrylamide, N-alkylacrylamide with 1-10 Catoms in the alkyl group, N-2-hydroxyethyl acrylamide, N-2-hydroxypropylacrylamide or methacrylamide, N-2-hydroxyethyl methacrylamide,N-2-hydroxypropyl methacrylamide, acrylonitrile and methacrylonitrile.

Suitable di- or multifunctional cross-linking agents may be, but notbeing limited to ethylene glycol dimethacrylate, triethylene glycoldimethacrylate, tetraethylene glycol dimethacrylate, trimethylopropanetrimethacrylate, bisphenol A dimethacrylate, ethoxylate bisphenol Adimethacrylate, pentaerythritol tri- and tetrametacrylate,tetramethylene dimethacrylate, methylenebisacrylamide, methacryloxyethylvinyl carbonate, triallylcyanurate, methacryloxyethyl vinyl urea,divinyl benzene, diallyl itaconate, allyl methacrylate, diallylphtalate, polysiloxanylbisalkyl methacrylate and polyethylene glycoldimethacrylate.

Oligo- or macromeric structures of a non-toxic nature are preferred. Ofthese, PEG containing di- or multifunctional oligo-or macromers may beof special interest. In the present invention, polyethylene glycoldimethacrylate of an approximately molecular weight of 400 (PEG-DMA 400)and an approximately molecular weight of 1000 (PEG-DMA 1000) may bepreferred as cross-linking agent.

In a preferred embodiment of the invention the photoinitiator compriseswater-soluble inorganic peroxydisulphates, such as sodium, potassium orammonium peroxydisulphate.

The solution may further comprise one or more co-initiators. Theco-initiator may be in the form of transition metal ions.

Metal ions suitable for use as co-initiators may be any of thetransition metal ions, having at least two readily oxidation states.These include but are not being limited to ferric/ferrous,cupric/cuprous, ceric/cerous, cobaltic/cobaltous,vanadate(V)/vanadate(IV), permanganate and manganic/manganous.

Surprisingly, it is possible to obtain the fast and deep efficientcuring of the described polymer system by photodecomposition by UV-lightusing an initiator, i.e. a water-soluble inorganic peroxydisulphate,which may have been disclosed, as a thermal, redox or photoinitiator buthas not been utilized in a context similar to the invented methodpresented here. It is as such in small amounts a very efficientphotoinitiator for the graft copolymerisation and cross-linking of ahydrophilic saturated polymer system in presence of catalytic amounts ofa cross-linking agent. The curing can be further enhanced by using thephotoinitiator in combination with a ferrous co-initiator system(photo-Fenton like), which will enhance the initiation process bycreating more free radicals initiation species.

The photoinitiators may be water-soluble peroxy-group containingcompounds, preferably, but not being limited to the inorganicperoxydisulphates, such as sodium, potassium or ammoniumperoxydisulphate, used alone or in combination with a co-initiatorpreferably Fe²⁺. The peroxydisulphates are photodecomposed to sulphateradicals, which radicals initiate the cross-linking process by creatingPVP-polymer radicals through hydrogen abstraction and PEG-DMA radicalsvia the vinylic groups of dimethacrylate. Photoinitiators may be used inthe polymer mixture in an effective quantity from 0.1 to 5% w/w, inparticular 0.5 to 5% w/w.

To further speed up the process and add to the efficiency, the additionof a co-initiator like Fe²⁺ may give a higher initial concentration offree radicals. Fe²⁺ reduces peroxydisulphate into a sulphate ion and asulphate radical ion. Fe³⁺ is converted back to Fe²⁺ by photoreductionof the UV-light and Fe²⁺ is now further available for radical formationwith peroxydisulphate. The utilization of this photo-Fenton like systemserves dual purposes. Firstly, it creates the maximum amount of freeradicals in a positive feedback loop as there is both acting aphotodecomposition of peroxydisulphate into sulphate radicals (andhydroxyl radicals in water) while simultaneously Fe²⁺ reducesperoxydisulphate into a sulphate ion and a sulphate radical ion. Thephoto conversion of Fe³⁺ back to Fe²⁺ ensures that any excess ofperoxydisulphate will be converted into radicals.

Secondly, the stability of the hydrogel may be further improved by theaddition of Fe²⁺ and the photo-Fenton like reaction scheme, since Fe²⁺may initiate the decomposition of undesired peroxides which could beformed during the polymerisation process and which possibly could impairhydrogel stability.

As the present invention is based on photocuring in an aqueousenvironment a water-soluble photoinitiating system is preferred.However, any compound, which disintegrates into radicals when subjectedto radiation, may be used. A primary concern of choice is the toxicprofile of the photoinitiator.

The photoinitiator system in the present invention may in principle beused in combination with known water-soluble photoinitiators such asbenzophenone, acetophenone, fluorenone, benzaldehyde, propiophenone,anthraquinone, carbazol, 3 or 4-methylacetophenone, 3 or4-methoxybenzophenone, 4,4′-dimethoxybenzophenone, allylacetophenone,2,2′-diphenoxyacetophenone, benzoin, methylbenzoin ether, ethylbenzoinether, propylbenzoin ether, benzoin acetate, benzoinphenyl carbamate,benzoin acrylate, benzoinphenyl ether, benzoyl peroxide, dicumylperoxide, azo isobutyronitrile, phenyl disulphide, acyl phosphene oxideor chloromethyl anthraquinone as well as mixtures thereof.

Co-catalysts such as amines, for example triethanolamine, as well asother trialyl amines of trialkylol amines could be added. In principle,any compound typically used in photoinitiation as radical generators orco-catalysts may be used. Sulphur compounds, heterocycles, for example,imidazole, enolates, organo-metallics and other compounds, such asN-phenyl glycine.

Additionally, comonomers could be added to change the polymerisationprocess or the final properties of the hydrogel of the invention. Thesecomonomers include sulphoxide containing methacrylate, polyethyleneglycol (400) ether monomethacrylate and glycerol monomethacrylate. Alsoof interest are N-vinyl compounds, including N-vinylpyrrolidone, N-vinylacetamide, N-vinyl imidazole, N-vinyl caprolactam and N-vinyl formamide.A primary concern when including a cocatalyst or a comonomer is thetoxicity in the resulting hydrogel system.

The solvent of choice for the preparation of the cross-linked hydrogelin the present invention is water or buffered aqueous solutions.However, any solvent, which may have a favourable effect on thephotopolymerisation process or the working properties of the hydrogelsystem may be employed. Suitable solvents may be acetone, methyl ethylketone, methanol, ethanol, propanol, butanol, ethyl acetate, butylacetate, methylene chloride, toluol, THF, water and mixtures thereof.Again, the concern of any potential residual solvent toxicity in thefinished hydrogel is determining the choice of co-solvent. Water ispreferred as solvent due to the non-toxic properties, as well as nowashing or extraction of any toxic solvent from the resulting hydrogelmay be needed, when water is employed.

In one embodiment of the invention the hydrogel comprises one or moreplasticizers, preferably polyols. The plasticizers include, but are notbeing limited to polyols like glycerol, propylene glycol andpolyethylene glycols of various chain lengths.

The hydrogels may be prepared with a range of additives to obtainspecial chemical or physical characteristics. Surfactants may be addedfor stabilization purposes.

Polymeric material may be added for viscosity improvement of the polymersolutions: Cellulose derivatives, like methyl cellulose,hydroxymethylcellulose, hydroxypropyl cellulose, ethyl cellulose, sodiumcarboxymethyl cellulose, other polysaccharides like but not beinglimited to acacia gum, trachagant, alginate, carrageenan, xanthan,locust bean gum, chitosan, starch derivatives like carboxymethyl-starchor dextran.

Synthetic polymers which introduces complexation with the principlepolymers in the present invention may also be utilized to alter thephotocuring polymer solutions and include but are not being limited topolyacrylates and polymethacrylates. Solubilizers like cyclodextrins mayalso be added.

The gels may be provided with a supporting net or reinforcing layer. Thereinforcing layer may ease the handling of the hydrogel as well as thestrength of the gel is enhanced. The reinforcing layer may be in theform of a web or a net, or a non woven material such as polyester,polyamide polyethyl or polypropyl, fibres, woven fabrics such as gauze,or foils or films with an open space structure or the like. Thereinforcing layer may be incorporated in the hydrogel, or the hydrogelmay be laminated or casted onto the net.

The hydrogel may be provided with a backing layer. The backing layer maybe totally occlusive, liquid impervious but vapour permeable or it maybe of a type having higher water permeability when in contact withliquid water than when not in contact. The backing layer may be of anysuitable material known per se for use in the preparation of medicaldevices e.g. a foam, a non-woven or a polyurethane, polyethylene,polyester or polyamide film.

A suitable material for use as a backing layer is a polyurethane. Apreferred low friction film material is disclosed in U.S. Pat. No.5,643,187.

In one embodiment of the invention the hydrogel of the present inventionis conductive. This is obtained by adding electrolytes like variouskinds of inorganic salts or other conductive compounds.

The hydrogel according to the invention may comprise one or more activeingredients.

The hydrogel according to the invention may comprise one or more activeingredients, e.g. pharmaceutically active compounds.

The compounds may be immobilized on or within the hydrogel. Numeroustechniques exist including physical entrapment, electrostaticattraction, physical adsorption or absorption and chemical bonding maybe utilized. The active compound may be entrapped by conducting thephotopolymerisation of the polymer solutions in the presence of theactive compound. Alternatively, the active agent could be introducedafter curing by imbibition. In imbibition, the previously preparedhydrogel is placed in a solution containing the solute for an extendedperiod of time. Eventually, the solute diffuses into the hydrogel.

The hydrogel may be used as a transdermal delivery device for the localor systemic treatment of diseases and may be used as a matrix formicro—or nano particles containing an active pharmaceutical agent.

Examples of pharmaceutical medicaments includes a cytochine such as agrowth hormone or a polypeptide growth factor such as TGF, FGF, PDGF,EGF, IGF-1, IGF-2, colony stimulating factor, transforming growthfactor, nerve stimulating growth factor and the like giving rise to theincorporation of such active substances in a form being apt to localapplication in a wound in which the medicament may exercise its effecton the wound, other medicaments such as bacteriostatic or bactericidalcompounds, e.g. iodine, iodopovidone complexes, chloramine,chlorohexidine, silver salts such as sulphadiazine, silver nitrate,silver acetate, silver lactate, silver sulphate, silver sodiumthiosulphate or silver chloride, zinc or salts thereof, metronidazol,sulpha drugs, and penicillin's, tissue-healing enhancing agents, e.g.RGD tripeptides and the like, proteins, amino acids such as taurine,vitamins such ascorbic acid, enzymes for cleansing of wounds, e.g.pepsin, trypsin and the like, proteinase inhibitors ormetallo-proteinase inhibitors such as Illostat or ethylene diaminetetraacetic acid, cytotoxic agents and proliferation inhibitors for usein for example surgical insertion of the product in cancer tissue and/orother therapeutic agents which optionally may be used for topicalapplication, pain relieving agents such as lidocaine or chinchocaine,emollients, retinoids or agents having a cooling effect which is alsoconsidered an aspect of the invention.

The active ingredient may also comprise odour controlling or odourreducing material.

Materials and Methods EXAMPLE 1

20 g of polyvinyl-pyrrolidone (PVP K90) was mixed with 4 g ofpolyethylene-glycol dimethacrylate 1000 (PEG-DMA 1000) and 1 g sodiumperoxydisulphate in 75 g of 0.1 M citric acid/citrate buffer pH 6.0. Thepolymer solution was dispensed into a suitable mold in 5 mm thicknessand cured under UV-light. The hydrogel was UV-cured under a singleUV-lamp (specifications: 200 W/cm, microwave powered “D”-spectral typelamp with a conveyor speed of 0.4 m/min). A hydrogel sheet of 5 mmthickness was obtained.

The rheological properties of the gel was examined using dynamicoscillation rheology determining the viscoelastic moduli, G′ (Elasticmodulus) and G″ (Loss modulus) and tan delta (G″/G′) at a frequency of 1Hz, 25° C.

The equilibrium swelling was determined by swelling the cured hydrogelsin Milli-Q water for 24 hours and calculating the relative increase inuptake of water.

The viscoelastic moduli of this hydrogel was

G′=4588 Pa, G″=1110 Pa and tan delta=0.242

Equilibrium swelling=700%

Example 1 describes the preparation of a basic hydrogel of theinvention. It is seen that at hydrogel containing 75% water w/w isobtained with a high elastic moduli, a lower G″ which gives a tan deltavalue indicating a quite elastic system. Despite the high amount ofwater the hydrogel is still capable of absorbing water 7 times its ownweight.

EXAMPLE 2

20 g of polyvinyl-pyrrolidone (PVP K90) was mixed with 4 g ofpolyethylene-glcyol dimethacrylate 1000 (PEG-DMA 1000) and 1 g sodiumperoxydisulphate in 60 g of 0.1 M citric acid/citrate buffer pH 6.0. Tothis solution was added 10 ml of 5.0×10⁻⁴ M FeSO.sub.4 and 5 ml of1×10⁻³ M ascorbic acid. The polymer solution was dispensed into asuitable mold in 5 mm thickness and cured under UV-light. The hydrogelwas UV-cured under a single UV-lamp (specifications: See Example 1). Ahydrogel sheet of 5 mm thickness was obtained.

Rheological characterization as in Example 1.

G′=5300 Pa, G″=1200 Pa and tan delta=0,226

Equilibrium swelling=625%

The use of a co-initiator system for a possible improvement of curing ofthe hydrogel was examined. As a higher elastic modulus (G′), a lower tandelta and a lower equilibrium swelling is observed, this implies astronger and more cross-linked gel which is a result of a better curing.

EXAMPLE 3

10 g of polyvinyl-pyrrolidone K90 (PVP K90) is mixed with 10 gpolyvinyl-pyrrolidone K25 (PVPK25), 4 g of polyethylene-glycoldimethacrylate 1000 (PEG-DMA 1000) and 1 g sodium peroxydisulphate in 75g of 0.1 M citric acid/citrate buffer pH 6.0. The polymer solution wasdispensed into a suitable mold in 5 mm thickness and cured underUV-light. The hydrogel was UV-cured under a single UV-lamp(specifications: See Example 1). A hydrogel sheet of 5 mm thickness wasobtained.

Rheological characterization as in example 1.

G′=2400 Pa, G″=630 Pa and tan delta=0,262

Equilibrium swelling=800%

Examples 3 shows the use of shorter chained PVP in combination with theprinciple PVP K90 macromer. This produces a more soft gel compared tothe basic hydrogel and with a higher swelling ratio. Also the tackinessof the gel is increased.

EXAMPLE 4

20 g of polyvinyl-pyrrolidone-co-vinylacetat (VA64) is mixed with 4 g ofpolyethylene-glycol dimethacrylate 1000 (PEG-DMA 1000) and 1 g sodiumperoxydisulphate in 60 g of 0.1 M citric acid/citrate buffer pH 6.0. Thepolymer solution was dispensed into a suitable mold in 5 mm thicknessand cured under UV-light. The hydrogel was UV-cured under a singleUV-lamp (specifications: See Example 1). A hydrogel sheet of 5 mmthickness was obtained.

Rheological characterization as in Example 1.

G′=2500, G″=955 and tan delta=0,382

Equilibrium swelling=850%

Example 4 describes the use of a water-soluble copolymer ofvinylpyrrolidone and vinylacetat. Softness and tackiness are increased.Swelling is increased too.

EXAMPLE 5

20 g of polyvinyl-pyrrolidone K90 (PVP K90) was mixed 4 g ofpolyethylene glycol dimethacrylate 1000 (PEG-DMA 1000) and 1 g sodiumperoxydisulphate in 65 g of 0.1 M citric acid/citrate buffer pH 6.0. 10g of glycerol was added to this solution. The polymer solution wasdispensed into a suitable mold in 5 mm thickness and cured underUV-light. The hydrogel was UV-cured under a single UV-lamp(specifications: See Example 1). A hydrogel sheet of 5 mm thickness wasobtained.

Rheological characterization as in Example 1.

G′=3640 Pa G″=1120 Pa and tan delta=0,306

Equilibrium swelling=850%

Example 5 shows the addition of a polyol. The effect of this additive isa softer feel, an increase in tack, a higher degree of swelling ascompared to the basic hydrogel in Example 1. The permeability and waterloss is lowered.

EXAMPLE 6

10 g of polyvinyl-pyrrolidone K90 (PVP K90) was mixed with 4 g ofpolyethylene glycol dimethacrylate 1000 (PEG-DMA 1000) and 1 g sodiumperoxydisulphate in 60 g of 0.1 M citric acid/citrate buffer pH 6.0. Tothis solution was added 5 g of KCl.

The hydrogel was UV-cured under a single UV-lamp (specifications: SeeExample 1). A sheet hydrogel of 5 mm thickness was obtained.

Rheological characterization as in Example 1.

G′=2810 Pa, G″=1070 and tan delta=0,380

Equilibrium swelling=725%

Example 6 shows a basic hydrogel with the addition of an electrolyte toproduce a conductive hydrogel for possible use in electrodes. Comparedto the basic hydrogel in Example 1, the presence of 5% w/w of KCl makesthe resulting gel softer and a little less elastic. However, thehydrogel has a bit more preferred tack.

EXAMPLE 7

Cytotoxicity Test

A hydrogel prepared according to example 1 was tested for cytoxicityaccording to ISO standard 1993-5 described in USP 24 “elution assay”.

No cell toxicity was observed.

EXAMPLE 8

Residual PEG-DMA

A hydrogel prepared according to Example 1 was tested for residualPEG-DMA (MAA). The gel was swollen in water in a vial and homogenized inthis vial. The vial was centrifuged and the supernatant was analyzed forMAA via a reesterification-process and HS-GCMS. The amount of PEG-DMA is<25 ppm (5 ppm MAA-equivalents).

EXAMPLE 9

A Multilayer Hydrogel

A hydrogel was prepared according to Example 1. A polymer solutionaccording to Example 4 was placed on the hydrogel and cured under thesame standard conditions UV-light. A further layer consisting of thepolymer solution described in Example 5 was then put on the top andcured creating a three-layered gel structure.

This multilayer gel having three different swelling zones may beutilized as drug delivery vehicle for the controlled release of apharmacological active compound.

EXAMPLE 10

Hydrogel with Incorporated Support.

A hydrogel according to Example 1 was prepared incorporating a foil ofan open space structure. The foil was placed directly in the polymersolution, which was then cured according to Example 1. It was possibleto cure the polymer solution with net directly to obtain hydrogel withincorporated supporting foil.

Such a hydrogel system may be suitable for use in wound care, forexample for burn wounds.

EXAMPLE 11

Hydrogel with a Backing Layer

A polymer solution according to Example 1 was prepared and placed on apolyurethane (PU) film. The polymer solution was cured in accordance toExample 1 and a resulting hydrogel immobilized on the PU-film wasobtained, thus demonstrating that the hydrogel may be prepared andimmobilized directly on a suitable surface.

EXAMPLE 12

20 g of polyvinyl-pyrrolidone K90 (PVP K90) was mixed with 5 gpolyvinyl-pyrrolidone K25 (PVPK25), 2 g of polyethylene-glycoldimethacrylate 1000 (PEG-DMA 1000) and 0.2 g sodium peroxidisulphate in75 g of 0.1 M citric acid/citrate buffer pH 6.0. The polymer solutionwas dispensed into a suitable mold in 5 mm thickness and precured undera single UV-lamp (specifications: See Example 1) with a conveyor speedof 0.6 m/min. A soft hydrogel sheet of 5 mm thickness was obtained. Thishydrogel was post-cured and sterilized with electron beam irradiation(50 KGy).

Rheological characterization as in Example 1.

G′=3955 Pa, G″=876 Pa and tan delta=0,221

Equilibrium swelling=675%

Example 12 demonstrates a curing method in which UV-curing is used incombination with electron beam irradiation. The hydrogel is procuredlightly to a soft hydrogel and then subjected to electron beamirradiation, which cure the hydrogel to its final specifications whileat the same time serving as a sterilization method.

1. A method of preparing a cross-linked hydrogel by graftpolymerization, comprising the steps of: (1) preparing an aqueoussolution having at least one saturated hydrophilic polymer component;(2) adding a cross-linking agent at a concentration between about 1 wt %and about 30 wt %, wherein the cross-linking agent is selected from thegroup consisting of di- or multifunctional acrylates and methacrylates;(3) adding a water soluble peroxydisulphate photoinitiator having aconcentration of between about 0.1 wt % to 1.25 wt %; (4) initiating thecrosslinking of the polymer component in said solution by exposing theaqueous solution to ultraviolet (UV) irradiation; and wherein the curingtime for the hydrogel is less than about 5 minutes.
 2. The method ofclaim 1, wherein the aqueous solution comprises at least two saturatedhydrophilic polymers.
 3. The method of claim 1, wherein the watersoluble peroxydisulphate is selected from the group consisting of sodiumperoxydisulphate, potassium peroxydisulphate, and ammoniumperoxydisulphate.
 4. The method of claim 1, wherein the aqueous solutionfurther comprises at least one co-initiator selected from the groupconsisting of multivalent transition metal ions.
 5. The method of claim1, wherein the hydrophilic polymer component is selected from the groupconsisting of polymers of cellulose derivatives, polysaccharides,polyvinyl pyrolidone, polyvinyl alcohol, polyacrylic acid, poly(methylvinyl ether/maleic anhydride), poly(meth)acrylic acid or polyethyleneglycol, copolymers thereof and blends thereof.
 6. The method of claim 1,wherein the hydrophilic polymer component comprises poly-vinylpyrrolidone or copolymers of polyvinyl pyrrolidone with cellulosederivatives, polysaccharides, polyvinyl alcohol, polyacrylic acid,poly(methyl vinyl ether/maleic anhydride), poly(meth)acrylic acid orpolyethylene glycol and blends thereof with cellulose derivatives,polysaccharides, polyvinyl alcohol, polyacrylic acid, poly(methyl vinylether/maleic anhydride), poly(meth)acrylic acid or polyethylene glycol.7. The method of claim 1, wherein the aqueous solution further comprisesone or more plasticizers.
 8. The method of claim 1, wherein thecross-linked hydrogel is in the form of a sheet.
 9. A composition forthe preparation of a cross-linked hydrogel by photopolymerization, thecomposition comprising at least one saturated hydrophilic polymercomponent, a cross-linking agent at a concentration between about 1 wt %and about 30 wt %, wherein the crosslinking agent is selected from thegroup consisting of di- and multifunctional acrylates or methacrylates,and a water soluble peroxydisulphate photoinitiator having aconcentration of between about 0.1 wt % to 1.25 wt %, said compositionbeing used in the method of claim
 1. 10. The composition according toclaim 9, wherein the composition comprises at least two saturatedhydrophilic polymers.
 11. A method of preparing a cross-linked hydrogelby graft polymerization, comprising the steps of: (1) preparing anaqueous solution having at least one saturated hydrophilic polymercomponent, (2) adding a cross-linking agent at a concentration betweenabout 1 wt % and about 30 wt %, wherein the cross-linking agent isselected from the group consisting of di- or multifunctional acrylatesor methacrylates; (3) adding a water soluble peroxydisulphatephotoinitiator having a concentration of between about 0.1 wt % to 1.25wt %; (4) initiating the crosslinking of the polymers in said solutionby exposing the aqueous solution to UV irradiation; (5) allowing thehydrogel to cure in the form of a sheet or coating having a thicknessbetween 10 μm to 2 cm; and wherein the curing time for the hydrogel isless than about 5 minutes.